碳酸环醇是中性保留葡萄糖酶抑制剂
Thomas J M Beenakker, Dennis P A Wander, Wendy A Offen1
1Department of Chemistry, University of York , Heslington, York, YO10 5DD, U.K.
Journal of the American Chemical Society
|May 3, 2017
概括
我们设计了一种新型的碳环醇抑制剂,
科学领域:
- 生物化学
- 酶抑制剂的设计
- 计算化学
背景情况:
- 糖酶是参与各种生物过程的关键酶.
- 开发特定的葡萄糖酶抑制剂对于治疗应用很重要.
- 过渡状态模拟是一种成功的策略,用于设计强大的酶抑制剂.
研究的目的:
- 设计和合成一种新型的卡巴-环醇类似物作为保留β-葡萄糖酶抑制剂.
- 使用计算方法研究环抑制剂的构造偏好.
- 评估新化合物对Thermotoga maritima TmGH1β- 葡萄糖酶的抑制活性.
主要方法:
- 一开始的元动力学模拟来分析构造的自由能景观.
- 用N- ((4-azidobutyl) carboxamide部分合成碳酸环醇.
- 酶抑制测定和三维结构分析.
主要成果:
- 模拟显示了环胺抑制剂中H3转变态构成的强烈偏差.
- 卡巴- 环醇具有强大的TmGH1β- 葡萄糖酶抑制作用,Ki为8. 2nM.
- 结构分析证实了H3的结合,验证了设计策略.
结论:
- 卡巴环醇类似物是Thermotoga海洋TmGH1β- 葡萄糖酶的强有力的抑制剂.
- 由环基单元诱导的构造应变增强了抑制剂的结合亲和力.
- 这种方法为开发新型紧结酶抑制剂提供了有前途的策略.
相关概念视频
Oral Hypoglycemic Agents: α-Glucosidase Inhibitors
684
α-glucosidase inhibitors, including acarbose (Precose), miglitol (Glyset), and voglibose (Voglib) (primarily available in Asia), are drugs that control blood sugar levels by delaying the digestion of starch and disaccharides. They achieve this by inhibiting α-glucosidase enzymes in the intestine, which slow the absorption of carbohydrates in the intestine, which in turn leads to a prolonged release of the glucoregulatory hormone GLP-1 from intestinal L-cells.
Acarbose and miglitol are...
Acarbose and miglitol are...
684
Dipeptidyl Peptidase 4 Inhibitors
787
Dipeptidyl peptidase 4 (DPP-4) is a serine protease widely distributed in the body. It's involved in the inactivation of GLP-1 and GIP hormones, which are crucial for insulin regulation. DPP-4 inhibitors, such as sitagliptin (Januvia), saxagliptin (Onglyza), linagliptin (Tradjenta), alogliptin (Nesina), and vildagliptin (Galvus), help increase the proportion of active GLP-1, enhancing insulin secretion. These inhibitors work by competitively binding to DPP-4. This binding causes a...
787
Oral Hypoglycemic Agents: Biguanides and Glitazones
739
Biguanides, particularly metformin (Glucophage), are insulin sensitizers that enhance glucose uptake, thereby reducing insulin resistance. Unlike sulfonylureas, metformin doesn't prompt insulin secretion, which helps to curb hypoglycemia risk. Metformin is beneficial in treating conditions like polycystic ovary syndrome due to its insulin-resistance reduction capability. The drug's primary action involves curtailing hepatic gluconeogenesis, a significant contributor to high blood...
739
Oral Hypoglycemic Agents: Glinides
760
Repaglinide (Prandin) and Nateglinide (Starlix), known as glinides, are oral insulin secretagogues that stimulate insulin release from pancreatic β cells by closing the ATP-sensitive potassium channels (KATP channel). Repaglinide controls insulin release from pancreatic β cells by managing potassium efflux. It shares two binding sites with sulfonylureas and also has a unique site, indicating overlapping mechanisms of action. With a rapid onset and a 4-7 hour duration, it effectively...
760
Glucagon-like Receptor Agonists
1.1K
Incretins include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which stimulate insulin secretion post-meals. In type 2 diabetes, GIP's efficacy is reduced, making GLP-1 a viable drug target. GIP originates from preproGIP.
GLP-1, when administered in high doses intravenously, triggers insulin secretion, inhibits glucagon release, slows gastric emptying, reduces food intake, and restores normal insulin secretion. However, its rapid inactivation by...
GLP-1, when administered in high doses intravenously, triggers insulin secretion, inhibits glucagon release, slows gastric emptying, reduces food intake, and restores normal insulin secretion. However, its rapid inactivation by...
1.1K
Bioavailability Enhancement: Drug Stability Enhancement and GI Retention
281
Improving a drug's stability in the gastrointestinal (GI) tract is paramount for enhancing its bioavailability and therapeutic effectiveness. Various strategies are employed to protect the drug from the harsh gastric milieu and to ensure its release and absorption at the desired site within the GI tract.Polymer coatings are one such method used to shield drugs from the stomach's acidic environment. By preventing premature drug release, these coatings improve the bioavailability of unstable...
281


